Publications by authors named "Tim Bishop"

19 Publications

  • Page 1 of 1

Is the AO spine thoracolumbar injury classification system reliable and practical? a systematic review.

Acta Orthop Belg 2021 Mar;87(1):181-190

Controversy surrounding the classification of thoracolumbar injuries has given rise to various classification systems over the years, including the most recent AOSpine Thoracolumbar Injury Classification System (ATLICS). This systematic review aims to provide an up-to-date evaluation of the literature, including assessment of a further three studies not analysed in previous reviews. In doing so, this is the first systematic review to include the reliability among non-spine subspecialty professionals and to document the wide variety between reliability across studies, particularly with regard to sub-type classification. Relevant studies were found via a systematic search of PubMed, EBESCO, Cochrane and Web of Science. Data extraction and quality assessment were conducted in line with Cochrane Collaboration guidelines. Twelve articles assessing the reliability of ATLICS were included in this review. The overall inter-observer reliability varied from fair to substantial, but the three additional studies in this review, compared to previous reviews, presented on average only fair reliability. The greatest variation of results was seen in A1 and B3 subtypes. Least reliably classified on average was A4 subtype. This systematic review concludes that ATLICS is reliable for the majority of injuries, but the variability within subtypes suggests the need for further research in assessing the needs of users in order to increase familiarity with ATLICS or perhaps the necessity to include more subtype-specific criteria into the system. Further research is also recommended on the reliability of modifiers, neurological classification and the application of ATLICS in a paediatric context.
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March 2021

Tranexamic acid use in a patient with sickle cell disease undergoing posterior scoliosis correction surgery: safely mitigating bleeding and vaso-occlusive crises.

J Surg Case Rep 2021 Jan 29;2021(1):rjaa559. Epub 2021 Jan 29.

St George's University Hospital NHS Foundation Trust, London.

A 15-year-old female with 2-year post-menarchal adolescent idiopathic scoliosis and sickle cell disease (SCD) underwent posterior scoliosis correction surgery. SCD is associated with higher rates of surgical complications, and these patients require careful management to prevent vaso-occlusive sickle cell crises (VOSCC); scoliosis correction surgery can be associated with high morbidity and mortality, including significant blood loss. Multiple techniques were employed to successfully prevent VOSCC in this patient including a preoperative transfusion, meticulous haemostasis at osteotomy sites, not performing a costoplasty despite presence of a rib hump, maintenance of intraoperative mean arterial pressure below 70 mmHg, aggressive postoperative hydration and the use of intraoperative tranexamic acid (TXA). This is the first reported case of the use of TXA in a patient with SCD and scoliosis correction surgery. A satisfactory correction was achieved with a longer than average inpatient stay due to non-sickle cell pain and protracted wound ooze.
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http://dx.doi.org/10.1093/jscr/rjaa559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850132PMC
January 2021

An assessment of the distance between the phrenic nerve and major intrathoracic structures.

J Thorac Dis 2019 Aug;11(8):3443-3448

Department of Anatomy, Edwards Via College of Osteopathic Medicine, Spartanburg, SC, USA.

Background: There is a lack of consensus in the literature regarding phrenic nerve proximity to thoracic structures at the level of the diaphragm. This study was undertaken to provide thoracic surgeons data on phrenic nerve location in order to reduce iatrogenic injury during invasive surgery.

Methods: Bilateral thoracic dissection was performed on 43 embalmed human cadavers (25 males; 18 females) and data was obtained from 33 left and 40 right phrenic nerves. The site of phrenic nerve penetration into the diaphragm was identified. Calipers were used to measure the distance from each phrenic nerve to the: inferior vena cava (IVC), descending aorta, esophagus, lateral thoracic wall and anterior thoracic wall.

Results: Mean thoracic diameter of male cadavers was significantly greater than that of female cadavers (P value <0.0001). There was no statistically significant difference between the distances from each phrenic nerve to visceral structures between males and females, except regarding the distance from the right phrenic nerve to the anterior thoracic wall where males exhibited significantly greater distances (P value =0.0234).

Conclusions: This study provides important data on phrenic nerve proximity to intrathoracic structures in an effort to help reduce iatrogenic injury during procedures within the thoracic cavity. Although males had a significantly larger thoracic diameter than females, the only statistically significant difference showed that the right phrenic nerve is deeper in the thoracic cavity in males. As this nerve passes closer to visceral structures it may be more susceptible to damage from pathology in surrounding vessels. This may explain the increased incidence of right phrenic nerve damage due to aortic aneurysm in males reported in the literature.
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http://dx.doi.org/10.21037/jtd.2019.07.75DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753454PMC
August 2019

Pedicle distraction increases intervertebral and spinal canal area in a cadaver and bone model.

SICOT J 2018 4;4:15. Epub 2018 May 4.

Department of Orthopaedics, St Georges Hospital, Blackshaw Road, London SW17 0QT, UK.

Introduction: Lumbar spinal stenosis is degenerative narrowing of the spinal canal and/or intervertebral foramen causing compression of the spinal cord and nerve roots. Traditional decompression techniques can often cause significant trauma and vertebral instability. This paper evaluates a method of increasing pedicle length to decompress the spinal and intervertebral foramen, which could be done minimally invasive.

Methods: Three Sawbone (Sawbones Europe, Sweden) and 1 cadaveric lumbar spine underwent bilateral pedicle distraction at L4. A pedicle channel was drilled between the superior articular process and transverse process into the vertebral body. The pedicles underwent osteotomy at the midpoint. Screws were inserted bilaterally and fixated distraction of 0 mm, 2 mm, 4 mm and 6 mm. CT images were taken at each level of distraction. Foramen area was measured in the sagittal plane at L3/4. Spinal canal area was measured at L4 in the axial images. The cadaver was used to evaluate safety of osteotomy and soft tissue interactions preventing distraction. Statistical analysis was by student paired t-test and Pearson rank test.

Results: Increasing distraction led to greater Spinal canal area. From 4.27 cm to 5.72 cm (p = 0.002) with 6 mm distraction. A Maximal increase of 34.1%. Vertebral foramen area also increased with increasing pedicle distraction. From 2.43 cm to 3.22 cm (p = 0.022) with 6 mm distraction. A maximal increase of 32.3%. The cadaver spinal canal increased in area by 21.7%. The vertebral foramen increased in area by 36.2% (left) and 22.6% (right).

Discussion: For each increase in pedicle distraction the area of the spinal and vertebral foramen increases. Pedicle distraction could potentially be used to alleviate spinal stenosis and root impingement. A potential osteotomy plane could be at the midpoint of the pedicle with minimal risk to nerve roots and soft tissue restrictions to prevent distraction.
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http://dx.doi.org/10.1051/sicotj/2018009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935471PMC
May 2018

Large-scale Sequencing of Testicular Germ Cell Tumour (TGCT) Cases Excludes Major TGCT Predisposition Gene.

Eur Urol 2018 06 9;73(6):828-831. Epub 2018 Feb 9.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; William Harvey Research Institute, Queen Mary University, London, UK; Department of Clinical Genetics, Guys and St Thomas NHS Foundation Trust, London, UK; National Cancer Registration and Analysis Service, Public Health England, London, UK. Electronic address:

Testicular germ cell tumour (TGCT), the most common cancer in young men, has a significant heritable basis that has long raised questions as to the existence of underlying major high-penetrance susceptibility gene(s). To determine the contribution of rare gene mutations to the inherited risk of TGCT, we analysed germline whole-exome data for 919 TGCT cases and 1609 cancer-free controls. We compared frequencies between TGCT cases and controls of rare (<1%) and low-frequency (1-5%) coding variants (1) individually and (2) collapsed at the gene level via burden testing (T1, disruptive; T2, all deleterious; and T3, all nonsynonymous) using Fisher's exact test with Bonferroni correction of significance thresholds. No individual variant or individual gene showed a significant association with TGCT after correction for multiple testing. In the largest whole-exome sequencing study of testicular cancer reported to date, our findings do not support the existence of a major high-penetrance TGCT susceptibility gene (of odds ratio >10 and allele frequency [combined]>0.01%). Owing to its power, this study cannot exclude the existence of susceptibility genes responsible for occasional TGCT families or of rare mutations that confer very modest relative risks. In concert with findings from genome-wide association studies, our data support the notion that inherited susceptibility is largely polygenic with substantial contribution from common variation.

Patient Summary: In the largest study of its kind, we sequenced ∼20 000 genes in 919 men with testicular germ cell tumour (TGCT) and 1609 TGCT-free individuals and found no evidence of a single major gene underlying predisposition to TGCT (in the manner of BRCA1 for breast cancer). Instead, familial risk of TGCT is likely to be due to varying dosages of hundreds of minor genetic factors.
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http://dx.doi.org/10.1016/j.eururo.2018.01.021DOI Listing
June 2018

The clinicopathological and gene expression patterns associated with ulceration of primary melanoma.

Pigment Cell Melanoma Res 2015 Jan 1;28(1):94-104. Epub 2014 Oct 1.

Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.

Ulceration of primary melanomas is associated with poor prognosis yet is reported to predict benefit from adjuvant interferon. To better understand the biological processes involved, clinicopathological factors associated with ulceration were determined in 1804 patients. From this cohort, 348 primary tumor blocks were sampled to generate gene expression data using a 502-gene cancer panel and 195 blocks were used for immunohistochemistry to detect macrophage infiltration and vessel density. Gene expression results were validated using a whole genome array in two independent sample sets. Ulceration of primary melanomas was associated with more proliferative tumors, tumor vessel invasion, and increased microvessel density. Infiltration of tumors with greater number of macrophages and gene expression pathways associated with wound healing and up-regulation of pro-inflammatory cytokines suggests that ulceration is associated with tumor-related inflammation. The relative benefit from interferon reported in patients with ulcerated tumors may reflect modification of signaling pathways involved in inflammation.
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http://dx.doi.org/10.1111/pcmr.12315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276506PMC
January 2015

Vitamin D and melanoma.

Dermatoendocrinol 2013 Jan;5(1):121-9

Section of Epidemiology and Biostatistics; University of Leeds; Leeds, UK.

Recreational sun exposure and sunburn are causal for melanoma but the risk is strongly genetically determined. Health promotion advice about sun protection should be aimed at susceptible individuals (pale skin, freckles, large numbers of melanocytic nevi and a family history). We discuss here the evidence that sun-sensitive people have lower vitamin D levels and that, in practice, it is very difficult for such individuals to achieve sufficient levels without supplementation in the UK at least. We conclude that melanoma susceptible sun-avoidant individuals should be advised to avoid insufficiency by supplementation. Vitamin D is anti-proliferative in vitro for some melanoma cell lines. In a large melanoma cohort we have observed that lower serum 25-hydroxyvitamin D2/D3 levels at diagnosis were associated with thicker tumors and poorer prognosis (study as yet not validated). In the UK, melanoma patients commonly have sub-optimal 25-hydroxyvitamin D2/D3 levels at and post diagnosis; we discuss approaches to management of such patients based on some new data from our group.
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http://dx.doi.org/10.4161/derm.25244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3897580PMC
January 2013

Chemoprevention in Lynch syndrome.

Fam Cancer 2013 Dec;12(4):707-18

Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK,

CAPP1 tested aspirin 600 mg/day and/or resistant starch 30 g/day in 200 adolescent FAP carriers. Aspirin treatment resulted in a non-significant reduction in polyp number and a significant reduction in polyp size among patients treated with aspirin for more than 1 year. CAPP2 RCT used the same interventions in 937 Lynch syndrome patients, the first RCT to have cancer prevention as the primary endpoint. Aspirin did not reduce the risk of colorectal neoplasia in a mean treatment period of 29 months but double blind post intervention follow-up has revealed 48 participants developed 53 CRCs. Per protocol analysis showed 63% fewer colon cancers with aspirin (p = 0.008) apparent from 4 years, with a similar effect on other LS cancers. Resistant starch was not beneficial at long term followup. CAPP3 will involve a double blind dose non-inferiority trial comparing 100, 300 or 600 mg daily in 3,000 gene carriers. We can now recommend aspirin in people at high risk of colorectal cancer.
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http://dx.doi.org/10.1007/s10689-013-9650-yDOI Listing
December 2013

Evaluation of PAX3 genetic variants and nevus number.

Pigment Cell Melanoma Res 2013 Sep 4;26(5):666-76. Epub 2013 Jul 4.

Melanoma Unit, Department of Dermatology Hospital Clínic de Barcelona, IDIBAPS, Barcelona University, Barcelona, Spain.

The presence of a high nevus number is the strongest phenotypic predictor of melanoma risk. Here, we describe the results of a three-stage study directed at identifying risk variants for the high nevus phenotype. At the first stage, 263 melanoma cases from Barcelona were genotyped for 223 single-nucleotide polymorphisms (SNPs) in 39 candidate genes. Seven SNPs in the PAX3 gene were found to be significantly associated with nevus number under the additive model. Next, the associations for seven PAX3 variants were evaluated in 1217 melanoma cases and 475 controls from Leeds; and in 3054 healthy twins from TwinsUK. Associations with high nevus number were detected for rs6754024 (P values < 0.01) in the Barcelona and Leeds datasets and for rs2855268 (P values < 0.01) in the Barcelona and the TwinsUK sets. Associations (P values < 0.001) in the opposite direction were detected for rs7600206 and rs12995399 in the Barcelona and TwinsUK sets. This study suggests that SNPs in PAX3 are associated with nevus number, providing support for PAX3 as a candidate nevus gene. Further studies are needed to examine the role of PAX3 in melanoma susceptibility.
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http://dx.doi.org/10.1111/pcmr.12130DOI Listing
September 2013

Lynch syndrome: history, causes, diagnosis, treatment and prevention (CAPP2 trial).

Dig Dis 2012 23;30 Suppl 2:39-47. Epub 2012 Nov 23.

Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, UK.

Hereditary cancer due to pathological mutations in the mismatch repair gene family is now known as Lynch syndrome and affects at least 1 in 1,000 people, resulting in a 30-50% cancer risk most often involving the colorectum and endometrium. Annual or biennial colonoscopy reduces cancer deaths and many offer gynaecological surveillance, but most other associated cancers are not amenable to early detection. As microsatellite instability testing and tumour immunohistochemistry become routine, case finding will improve. Our recent demonstration that 600 mg aspirin per day for at least 2 years reduces the cancer burden by 63% after a 3-year lag period reinforces the need to identify gene carriers and introduce them to chemoprevention. CaPP3 will test different doses of aspirin in at least 3,000 gene carriers to determine whether low-dose aspirin is as effective.
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http://dx.doi.org/10.1159/000341892DOI Listing
June 2013

Genetics, inheritance and strategies for prevention in populations at high risk of colorectal cancer (CRC).

Recent Results Cancer Res 2013 ;191:157-83

Institute of genetic medicine, Centre for Life Central Parkway, Newcastle Upon Tyne, UK.

Hereditary forms of colorectal cancer account for less than 5 % of colorectal cancer but attract disproportionate attention because they offer an opportunity for effective surgical prophylaxis, influence the health of the wider family and give insight into the critical pathways of carcinogenesis. Familial Adenomatous Polyposis (FAP) due to loss of the APC gene and Lynch syndrome or Hereditary Non-Polyposis Colon Cancer (HNPCC) due to breakdown in MisMatch Repair are the principal syndromes of broader interest and both have been the subject of chemoprevention trials. There has been a longstanding interest in non-steroidal anti inflammatories in FAP where trials have shown regression of polyps with the "pro drug"sulindac and the selective COX2 inhibitors though impact on long-term cancer risk is not confirmed. The CAPP1 trial focused on two interventions in a factorial design, aspirin and resistant starch or fermentable fibre. Resistant starch is not absorbed in the small intestine and undergoes colonic fermentation to short-chain fatty acids including butyrate which have anti-cancer effects. Polyposis registry clinicians across Europe recruited adolescents with FAP to receive aspirin (600 mg as 2 tablets/d) and/or 30 g as 2 sachets/d in a 1:1 blend of potato starch and high amylose maize starch [Hylon VII]) with placebo control for at least a year or until surgery before age 21. Fifty-nine percent (133/227) of recruits had a baseline and at least one other endoscopy. After a median of 17 months , the primary endpoint of a risk of an increased polyp number in the rectum and sigmoid colon was not significantly reduced in either treatment group with relative risks of 0.77 (aspirin; 95 % CI, 0.54-1.10;) and 1.05 (RS; 95 % CI, 0.73-1.49. The diameter of the largest polyp detected tended to be smaller in the aspirin arm. The planned subgroup analyses of patients who elected to continue on study for more than one year found a significant reduction in the size of the largest polyp in the aspirin versus non-aspirin group (p = 0.02), Mean crypt length decreased significantly over time on study in the two combined RS groups, compared with the two combined non-RS groups (p < 0.0001 for interaction), in a model of the interaction between intervention and time. In CAPP2, 1009 Lynch syndrome gene carriers were recruited from 43 international centres. 937 commenced intervention: 600 mg enteric coated aspirin and/or 30grams of the resistant starch Novelose in a 2 by 2 factorial placebo controlled design. After a mean of 29 months, intervention, there was no evidence that either agent influenced development of colonic neoplasia. However, the design included double blind follow-up for at least 10 years. After a mean of 55.7 months, and despite regular colonoscopy and polyp removal, 48 recruits developed CRC. Of these, 18 received aspirin and 30 received AP; the HR for CRC for aspirin was 0.63 (CI 0.35-1.13, p = 0.12). Five of the 48 people who developed CRC each had two primary colon cancers. Poisson regression analysis to allow for multiple primary events indicated a protective effect: IRR 0.56 (CI 0.32-0.99, p = 0.05). For those who took aspirin (or AP) for a minimum of 2 years (per protocol) the HR was 0.41 (CI 0.19-0.86 p = 0.02) and the IRR, 0.37 (CI 0.18-0.78 p = 0.008). Combined analysis of all LS cancers including CRC revealed a similar effect. On intention to treat analysis, the HR was 0.65 (CI 0.42-1.00, p = 0.05 and IRR was 0.59 (CI 0.39-0.90 p = 0.01), while the Per Protocol analysis HR was 0.45 (CI 0.26-0.79 p = 0.005,) and IRR was 0.42 (CI 0.25-0.72, p = 0.001). Adverse events in the aspirin and placebo groups were similar with 11 significant gastrointestinal bleeds or ulcers in the aspirin group and 9 in the placebo group. The evidence is now sufficient to recommend aspirin to all Lynch syndrome gene carriers. CAPP3 will recruit 3000 gene carriers into a dose inferiority study to test the relative benefits of 100mg, 300 or 600mg daily doses.
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http://dx.doi.org/10.1007/978-3-642-30331-9_9DOI Listing
November 2012

Genome-wide association study identifies novel loci predisposing to cutaneous melanoma.

Hum Mol Genet 2011 Dec 17;20(24):5012-23. Epub 2011 Sep 17.

Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

We performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 × 10(-10)). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma.
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http://dx.doi.org/10.1093/hmg/ddr415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298855PMC
December 2011

People of the British Isles: preliminary analysis of genotypes and surnames in a UK-control population.

Eur J Hum Genet 2012 Feb 10;20(2):203-10. Epub 2011 Aug 10.

Department of Oncology, University of Oxford, ORCRB, Headington, Oxford, UK.

There is a great deal of interest in a fine-scale population structure in the UK, both as a signature of historical immigration events and because of the effect population structure may have on disease association studies. Although population structure appears to have a minor impact on the current generation of genome-wide association studies, it is likely to have a significant part in the next generation of studies designed to search for rare variants. A powerful way of detecting such structure is to control and document carefully the provenance of the samples involved. In this study, we describe the collection of a cohort of rural UK samples (The People of the British Isles), aimed at providing a well-characterised UK-control population that can be used as a resource by the research community, as well as providing a fine-scale genetic information on the British population. So far, some 4000 samples have been collected, the majority of which fit the criteria of coming from a rural area and having all four grandparents from approximately the same area. Analysis of the first 3865 samples that have been geocoded indicates that 75% have a mean distance between grandparental places of birth of 37.3 km, and that about 70% of grandparental places of birth can be classed as rural. Preliminary genotyping of 1057 samples demonstrates the value of these samples for investigating a fine-scale population structure within the UK, and shows how this can be enhanced by the use of surnames.
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http://dx.doi.org/10.1038/ejhg.2011.127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260910PMC
February 2012

Replication of the recessive STBMS1 locus but with dominant inheritance.

Invest Ophthalmol Vis Sci 2009 Jul 14;50(7):3210-7. Epub 2009 Feb 14.

Section of Ophthalmology and Neuroscience, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom.

Purpose: Strabismus is a common eye disorder with a prevalence of 1% to 4%. Comitant strabismus accounts for approximately 75% of all strabismus, yet more is known about the less common incomitant disorders. Comitant strabismus is at least partly inherited, but only one recessive genetic susceptibility locus, on chromosome 7p, has been identified in one family. The purpose of this study was to determine the frequency of STBMS1 as a cause of primary nonsyndromic comitant esotropia (PNCE).

Methods: Twelve families were recruited within the UK Hospital Eye Service as children attended for treatment of PNCE. All consenting persons were clinically assessed, and DNA was sampled. Chromosome 7 microsatellite markers were genotyped in all 12 families, and LOD scores were calculated under recessive and dominant models.

Results: One family was linked to STBMS1; in three, linkage was significantly excluded; and the remainder were uninformative. Twenty-six members from three generations of the linked family were analyzed further. Five family members were defined as affected; two had esotropia with an accommodative element; and three underwent strabismus surgery and appeared to have had an infantile/early-onset esotropia. A maximum LOD score of 3.21 was obtained under a dominant mode of inheritance; a recessive model gave an LOD score of 1.2.

Conclusions: This study confirms that PNCE can result from sequence variants in an unknown gene at the STBMS1 locus. However, this locus accounts for only a proportion of cases, and other genetic loci remain to be identified. In contrast with the previously reported family, the pedigree described in this study is consistent with dominant rather than recessive inheritance at the STBMS1 locus.
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http://dx.doi.org/10.1167/iovs.07-1631DOI Listing
July 2009

The genetics of melanoma.

Br J Hosp Med (Lond) 2006 Jun;67(6):299-304

University of Leeds, Cancer Research, UK.

Melanoma is an increasingly common cancer and in order to direct preventative advice at those at risk, an understanding of susceptibility is crucial. This review summarizes what is known about common low-risk genes (such as those controlling red hair) and rare high-risk genes.
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http://dx.doi.org/10.12968/hmed.2006.67.6.21288DOI Listing
June 2006

Diet and genetic factors associated with iron status in middle-aged women.

Am J Clin Nutr 2005 Oct;82(4):813-20

Nutritional Epidemiology Group and the Biostatistics Group, Centre for Epidemiology and Biostatistics, University of Leeds, Leeds, United Kingdom.

Background: Gene mutations associated with iron overload have been identified. How food and nutrient intakes affect iron status in persons who may be at risk of iron overload because their genetic status is unknown.

Objective: The objective was to determine the relation between food and nutrient intakes, HFE genotype, and iron status. Foods and nutrients associated with iron stores, with adjustment for gene mutations associated with hemochromatosis, were explored.

Design: A prospective cohort of women aged 35-69 y (the UK Women's Cohort Study) provided information on diet through a questionnaire and food diary; 6779 women in the cohort provided cheek cell samples, blood samples, or both, which were genotyped for C282Y and H63D mutations, and 2489 women also had their iron status assessed. Relations between serum ferritin and iron intake were investigated by using multiple linear regression, with adjustment for potential confounders.

Results: The strongest dietary association with serum ferritin concentration was a positive association with heme iron and not with nonheme or total iron. Weaker positive associations were seen with red and white meat, and negative associations were seen with total energy and white and brown whole-meal bread, independent of genotype and other potential confounders. The effect of genotype on ferritin concentrations primarily occurred after menopause, at which time a strong interaction between genotype and heme iron intake was observed. Other factors associated with serum ferritin concentrations were age, body mass index, blood donation, menopausal status, and HFE genotype.

Conclusions: Postmenopausal women eating a diet rich in heme iron and who were C282Y homozygotes had the highest serum ferritin concentrations.
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http://dx.doi.org/10.1093/ajcn/82.4.813DOI Listing
October 2005

A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics.

Am J Hum Genet 2005 Aug 29;77(2):219-29. Epub 2005 Jun 29.

Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.
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http://dx.doi.org/10.1086/432377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1224525PMC
August 2005

Premature coronary artery disease shows no evidence of linkage to loci encoding for tissue inhibitors of matrix metalloproteinases.

J Hum Genet 2003 19;48(10):508-513. Epub 2003 Sep 19.

Institute for Cardiovascular Research, University of Leeds, Leeds General Infirmary, G-Floor, Jubilee Wing, Leeds, LS2 9JT, UK.

Tissue inhibitors of metalloproteinases (TIMP1, TIMP2, TIMP3) are naturally occurring inhibitors of matrix metalloproteinases (MMPs). It has been proposed that MMPs have a role in weakening the fibrous cap and subsequent plaque rupture. We hypothesized that TIMP polymorphisms could predispose to premature coronary artery disease. As a first step, we examined the relevant loci using a linkage approach. Sibling pairs recruited for the British Heart Foundation (BHF) Family Heart Study with premature coronary artery disease were examined. Two to three microsatellite markers were examined per TIMP gene. These markers were either intragenic or very close to the locus encoding for the gene. Products were analyzed by capillary gel electrophoresis. Single and multipoint linkage analysis based on the likelihood ratio test was performed using SPLINK and Mapmaker/Sibs software; 417 families were genotyped consisting of 385 sibling pairs, 27 trios, and five sets of four siblings. We were unable to detect linkage of premature coronary artery disease to loci encoding for TIMP1-3. Polymorphisms of the tissue inhibitors of MMP genes do not predispose to premature coronary artery disease in an epidemiologically significant way.
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http://dx.doi.org/10.1007/s10038-003-0067-6DOI Listing
January 2004

Can resistant starch and/or aspirin prevent the development of colonic neoplasia? The Concerted Action Polyp Prevention (CAPP) 1 Study.

Proc Nutr Soc 2003 Feb;62(1):51-7

Human Nutrition Research Centre, School of Clinical Medical Sciences, University of Newcastle, Newcastle upon Tyne NE1 7RU, UK.

Loss of function of the adenomatous polyposis coli (APC) tumour suppressor gene through truncating mutations or other means is an early event in most colo-rectal cancer (CRC). The APC gene encodes a large multifunctional protein that plays key roles in several cellular processes, including the wnt signalling pathway where an intact APC protein is essential for down regulation of beta-catenin. The APC protein also plays a role in regulation of cell proliferation, differentiation, apoptosis, cell-cell adhesion, cell migration and chromosomal stability during mitosis. Acquisition of a non-functional APC gene can occur by inheritance (in the disease familial adenomatous polyposis (FAP)) or by a sporadic event in a somatic cell. Whilst there is strong epidemiological evidence that variation in diet is a major determinant of variation in CRC incidence, conventional adenoma recurrence trials in sporadic cases of the disease have been relatively unsuccessful in identifying potentially protective food components. Since the genetic basis of CRC in FAP and in sporadic CRC is similar, intervention trials in FAP gene carriers provide an attractive strategy for investigation of potential chemo-preventive agents, since smaller numbers of subjects and shorter time frames are needed. The Concerted Action Polyp Prevention (CAPP) 1 Study is using a 2 x 2 factorial design to test the efficacy of resistant starch (30 g raw potato starch-Hylon VII (1:1, w/w)/d) and aspirin (600 mg/d) in suppressing colo-rectal adenoma formation in young subjects with FAP. Biopsies of macroscopically-normal rectal mucosa are also being collected for assay of putative biomarkers of CRC risk.
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http://dx.doi.org/10.1079/PNS2002236DOI Listing
February 2003
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